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July 19, 2017

Recently, at the 2017 UMDF Mitochondrial Medicine Symposium, Stealth BioTherapeutics shared very encouraging results from its second clinical trial for primary mitochondrial myopathy, the MMPOWER-2 study. Stealth is a Boston-based biopharmaceutical company developing therapeutics to treat mitochondrial dysfunction; its lead drug under investigation is elamipretide (previously known as Bendavia). Primary mitochondrial myopathy (PMM) is a genetically-acquired mitochondrial disease characterized by signs and symptoms of myopathy (debilitating muscle weakness, easy fatigability, exercise intolerance and pain). The Phase 2 MMPOWER-2 trial was conducted to evaluate safety, tolerability and efficacy of treatment using elamipretide in 30 adult (ages 16-65) patients with PMM. An overall assessment of the top-line MMPOWER-2 results showed benefit across multiple endpoints and is supportive of continuation toward a Phase 3 study in this patient population.

Patients enrolled in MMPOWER-2 previously participated in Stealth’s MMPOWER trial, designed to assess dosing, which demonstrated a dose-dependent improvement in distance walked in the 6-Minute walk test (6MWT) after 5 days of once daily intravenous administration of elamipretide or placebo. In MMPOWER-2, patients were randomized to once daily subcutaneous administration of elamipretide or placebo for a longer period of time (four weeks), and then, after a washout period, received the opposite treatment during a second four-week dosing period. Patients, their doctors and investigators at Stealth were unaware of which group patients belonged to during the trial and the subsequent assessments.

This type of study design, known as a randomized, double-blind, placebo-controlled crossover study, is considered a “gold standard” in clinical trials evaluating investigational drugs. Randomized controlled trials can be challenging in rare and orphan diseases because there simply are not as many patients available to participate, and there tend to be as many differences as there are similarities between patients who may have the same diagnosis (also known as heterogeneity).

Multiple endpoints, or outcomes, were considered and evaluated during the MMPOWER-2 trial in addition to the 6MWT, including the Neuro-QoL (Quality of Life in Neurological Disorders) measurement system, and a new patient-reported outcome tool, the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA), developed by Stealth specifically for this patient population. Other tools and measures for safety, tolerability and functional assessment were also applied.

Chuck Mohan, Executive Director of the United Mitochondrial Disease Foundation, comments “Clinical trials for rare diseases are challenging and we are very supportive of Stealth for their efforts to evaluate potential therapeutics in a meaningful, rigorous and scientific manner. The progress of the MMPOWER-2 trial provides hope to our global mitochondrial disease community. ”

The primary objective of the study was to evaluate the effect of a single daily subcutaneous dose of elamipretide for four weeks on a PMM patient’s walking distance, as measured by the 6MWT. Patients receiving elamipretide walked an average of 20 meters more than those receiving placebo at the end of the 4-week dosing period. In addition, those patients who were the most impaired at baseline demonstrated the greatest improvement.

Data gathered and analyzed for several other secondary endpoints is also informative and promising. Treatment with elamipretide resulted in statistically significant and clinically meaningful improvements in the Neuro-QOL Fatigue Short Form score and in the PMMSA Total Fatigue score. In other words, patients showed overall improvement in fatigue and in symptoms which impacted their daily quality of life and functional abilities. Patients also reported a statistically significant improvement in the PMMSA identified symptom most bothersome to them individually, such as tiredness, muscle weakness, muscle pain, abdominal discomfort, vision problems, or balance problems. Data also continued to demonstrate safety and tolerability of elamipretide, with the most common side effect being redness or itching at the injection site.

Kira Mann, CEO of MitoAction, is enthusiastic about these findings. “These results are very promising for patients struggling with fatigue, pain, and weakness due to mitochondrial myopathy. On behalf of patients and families with mitochondrial disease, we are excited about this data and continue to be supportive of future elamipretide studies.”

Stealth continues to be committed to developing mitochondrial therapeutics and engaging with the mitochondrial disease clinician and patient/family community. In March of 2017, Stealth initiated RePOWER, a prospective, observational study of patients with mitochondrial myopathy. RePOWER will assess approximately 300 PMM patients, ages 16-65, and will gather information about current symptoms, quality of life, functional abilities and medical history. Findings from MMPOWER, MMPOWER-2 and RePOWER will together help establish and inform a Phase 3 trial to continue to evaluate the potential efficacy, safety and tolerability of elamipretide. Stealth plans to launch its Phase 3 trial around the end of this year.

The executive director of the Foundation for Mitochondrial Medicine, Laura Stanley, has a child with mitochondrial disease. She states, “Results such as these demonstrate why it is so important for every patient and family with primary mitochondrial disease to be involved in these very important and groundbreaking studies. Together we are pioneering this field.”

We need your financial support to open the clinical and research program. Our goal is to raise $250,000 by year end which will provide both the clinical physician resources, including the key Nurse Navigator role and the research program elements for clinical certification of the Bioenergetics Health Index, a non-invasive blood test assessing mitochondrial function. This blood test has the potential to replace the traditional muscle biopsy and can also be applied to other neurodegenerative diseases, like Parkinson’s and Alzheimer’s, where mitochondrial dysfunction is a key contributor.

Read more details about the FMM program at UAB below.

About UABKnown for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is an internationally renowned research university and academic medical center, as well as Alabama’s largest employer, with some 23,000 employees, and has an annual economic impact exceeding $5 billion on the state. The five pillars of UAB’s mission include education, research, patient care, community service and economic development. UAB is a two-time recipient of the prestigious Center for Translational Science Award. Learn more at www.uab.edu.UAB: Knowledge that will change your world.

The FMM-Michael J. Fox Foundation co-funded research project led by Dr. Wolfdieter Springer from the Mayo Clinic Jacksonville shows promising results. Mutations in the gene for parkin are a common cause of early-onset Parkinson’s disease. Research into the biology of parkin has revealed an important role for the protein in maintaining healthy mitochondria. This has led to great interest in developing drugs that can activate parkin as a way to rescue cells from disease mechanisms that impair the normal regulation of mitochondria. In 2013, these efforts were given a major boost when several independent laboratories determined the structure of the parkin protein which led to greater understanding of how to design drugs that can target it. The schematic below is a representation of this structure. Researchers believe that drugs that target the ‘Ubl’ region may be able to activate the protein and allow it to help cells get rid of dysfunctional, unhealthy mitochondria.

Using the knowledge gleaned from the structure of the parkin protein, Dr. Springer is designing drug compounds that he believes can activate the protein. Dr. Springer presented initial results of his efforts and he has shown that a number of the drug compounds he designed appear to activate parkin and allow it to target mitochondria. As a next step, he will further optimize the compounds and also test whether they can rescue damaged mitochondria in laboratory models, a key step before deciding whether to move the compounds into further testing for Parkinson’s disease and mitochondrial disease.

Dr. Springer has also established several important collaborations with other key investigators working on parkin. These joint efforts should allow him to test additional compounds as well as gain access to other laboratory tests of parkin activity that will further strengthen his findings.

Novel Research for Mitochondrial-Directed Therapies to Address Alzheimer’s and Mitochondrial Disease

FMM and the Alzheimer’s Drug Discovery Foundation awarded a $200,000 grant to Dr. James Bennett of Virginia Commonwealth University. The purpose of this study is to determine if boosting mitochondrina function in mice engineered to develop aspects of Alzheimer’s disease will improve their memory and cognitive function. For these studies, Dr. Bennett is using a therapy that is in development by the biotechnology company, Gencia. This therapy, called rhTFAM, can be injected intravenously, and helps to stimulate the generation of new mitochondria, referred to as “mitochondria biogenesis.”

Dr. Bennett found that the rhTFAM treatment improved memory retention in the Alzheimer’s mice. Dr. Bennett and team are presently analyzing the brains of the rhTFAM-treated mice to look for effects on Alzheimer’s pathology and improvements in mitochondrial respiration and function. These positive initial finding on improving memory in mice have generated excitement about the potential of this therapy for Alzeimer’s patients as well as for other indications that exhibit mitochondria dysfunction. Often in mitochondrial disease, cognitive fatigue and impairments are some of the many symptoms patients exhibit. Gencia is enthusiastic about accelerating the development of rhTFAM into patient populations through clincial trials. The translational nature of Dr. Bennett’s research could have critical applications beyond Alzheimer’s disease to other related disorders that affect millions of Americans.

Fund The Cures – Support FMM!

The Foundation for Mitochondrial Medicine is dedicated to supporting the most promising treatments for the many forms of mitochondrial disease.

We support treatment based research, Institutional Review Board IRB-approved and/or FDA-approved studies. We are the first mitochondrial disease non-profit organization to have financially supported the first FDA-approved drug treatments, begun in 2009. In addition to functional MRI brain studies on cognitive fatigue, our grants are allowing new drug compounds to be tested, eventually leading to full clinical drug trials. Your support means momentum to accelerate entry into clinical trial phases, which will in turn propel research faster toward the cures.

One cure, one timeline, simply does not exist but with your help we will move forward faster.

Deep Brain Stimulation Shows Promise Against Alzheimer’s Disease

A German study using deep brain stimulation on patients, a treatment that can be used for patients suffering from Parkinson’s disease, showed some promise, with 4 out of 6 patients responding to treatment.

Deep brain stimulation is a procedure in which a brain pacemaker is implanted in the brain to send electrical impulses to specific parts of the brain. In the case of Alzheimer’s disease, the electrical impulses are sent to a region of the brain associated with the ability to think clearly and efficiently.

The use of deep brain stimulation as a treatment for Alzheimer’s disease is a relatively new idea. Despite the fact that 33% of seniors die with some form of Alzheimer’s or dementia, there is a startling lack of treatments in reversing the memory loss associated with these diseases. The German study provides hope for those suffering from this disease has opened doors for the improvement of the stimulators used for deep brain stimulation.

The Functional Neuromodulation study group announced last week that it had found 42 Alzheimer’s disease patients in the United States and Canada to study as a result of the success of the German study.

Due to the lack of a control group in the initial German study, the study by Functional Neuromodulation plans to specify what works and what doesn’t about the use of deep brain stimulation as a treatment option for Alzheimer’s disease patients.

Click here to learn more about the relationship between Alzheimer’s disease and mitochondrial dysfunction.

Researchers Fight for Alzheimer’s Cure

Alzheimer’s disease is the nation’s sixth leading cause of death and is predicted to affect 15 million elderly Americans by 2050.

Charles DeCarli is a neurologist and Alzheimer’s Disease Center director at UC Davis. Their clinic sees both patients and research study participants. They use a wide variety of treatments to attempt to stymie the damage this disease causes to the brain. The damage Alzheimer’s disease causes to the brain are startling.

According to Alz.org, brain atrophy is a prominent symptom in those affect. Parts of the brain that deal with memory and thought formation shrink, while fluid-filled spaces of the brain become larger.

DeCarli prescribes medications like Aricept and Nemenda, medications specifically geared to slowly memory loss in dementia associated with Alzheimer’s disease. However, the clinic is focusing on alternative methods of treatment to slow memory loss. Their clinic offers classes like Brain Fitness 101 to offer treatments emphasizing a healthy diet and brain exercises that can only postpone the decline in cognition.

The recent recession caused California, already the nation’s leader in researching Alzheimer’s disease, to cut funding to centers like the one DeCarli works. Despite the fact Alzheimer’s disease or other forms of dementia affect 1 in 3 seniors funding for this disease pales in comparison to diseases like cancer. Cancer researchers receive about $5 billion by the federal government each year, while Alzheimer’s researchers receive about $560 million.

DeCarli evaluates the research participants on a monthly basis, attempting to identify patterns in his patients’ deterioration. One of the more difficult parts of dealing with Alzheimer’s is noting the stages it attacks the brain. Working against a limited budget and time, his clinic uses autopsies of patients in an attempt to make sense of the way it affects research participants.

Alzheimer’s research is still greatly underfunded. You can make a difference by donating today.

What is the role of mitochondrial dysfunction in Alzheimer’s disease?

Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses associated with the etiology and underlying disease components of Alzheimer’s disease.2 Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role in the cause of Alzheimer’s disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to the onset and progression of Alzheimer’s disease.

Recogning the Importance Parkinson’s Awareness Month

FMM recognizes the importance of continued Parkinson’s disease research, education, programs and support groups, as this month marks the fifth year both houses of Congress have officially declared April Parkinson’s Awareness Month.

Parkinson’s disease is a progressive, neurodegenerative movement disorder. It worsens over time, and it is caused by the degeneration of nerve cells in the brain. The most prominent symptoms of Parkinson’s disease affect movement, although many other symptoms may also occur, some of which can be even more disabling than the movement symptoms.

Affecting 1 in every 500 people, Parkinson’s disease is a chronic progressive neurological disorder that takes an enormous physical, psychological and emotional toll on patients and their families.

Continues to support research to find better treatments, and eventually, a cure for Parkinson’s disease;

Recognizes the people living with Parkinson’s who participate in vital clinical trials to advance the knowledge of the disease;

The House of Representative similarly designated April to be Parkinson’s Awareness Month.

Parkinson’s Awareness Month presents an important opportunity to become better informed and to educate others about this neurological disorder. As our society continues to age, the number of individuals with Parkinson’s disease is expected to grow. In fact, the number of people dying from Parkinson’s disease has quadrupled in the past 20 years.

Mitochondrial Dysfunction and Parkinson’s Disease:
Scientists have accrued a large body of evidence confirming that mitochondria play an important role in the development of Parkinson’s disease. The most prominent symptoms of Parkinson’s disease are muscle trembling and weakness, which then progress to muscle immobility. These symptoms are the result of a decline of dopamine in the brain, which occurs as a result of loss of neurons that produce this vital neurotransmitter.

To learn more about how Parkinson’s disease and how it is related to mitochondrial disease, visit hopeflies.org.

Managing Mitochondrial Disease and College – Amanda Cameron’s Story

It took me 13 doctors to get diagnosed; I saw many types ranging from a rheumatologist to an allergist. My initial symptoms were chronic, moderate pain in my knees and nausea. As time passed, the pain spread up my back and to my shoulders. I began to experience neurological symptoms like tremors and progressive weakness that affected my joints, especially in my fingers.

Now, I am in a place where my health is stable and I want to give back. I hope to gain connections with other people affected by mitochondrial disease and advocate for this disease through the Foundation of Mitochondrial Medicine.

Amanda and a friend at a concert.

I’m a current freshman at the University of Georgia studying Mathematics and Genetics, with a Pre-Med emphasis. Managing my health at school is a challenge. Since school has started, some of my symptoms have come back. My pain has returned, and my energy has decreased. To manage my pain, I swim almost daily. Exercising coupled with a healthy diet allow me to increase my energy. This enables me to participate in events at my college and get the most out of campus life.

My priority at UGA is not letting my health dictate what kind of experiences I can have while I’m at college. Managing my time and getting adequate sleep all allow me to earn the good grades I need for medical school and experience events college has to offer. I also work in a lab at the UGA Department of Cellular Biology; this is one of my favorite on-campus experiences.

I refuse to let my energy disorder limit me, and I look forward to the challenges time will bring as I move through my college experience.

To learn more about mitochondrial disease and how you can help, visit hopeflies.org.

Austin Childers Dies after Long Battle with Mitochondrial Disease

Austin Childers

Austin Childers, whose battle with mitochondrial disease inspired thousands, passed away on Wednesday, February 26. Twenty-three year old Childers spent most of his days in medical facilities and through it all, maintained a positive outlook even in the midst of his overwhelmingly difficult situation. Throughout his 12-year battle, Childers underwent more than 70 surgeries and countless other medical procedures.

“Austin’s love for people was so deep,” his mother, Ashley Childers, said. “He just wanted people around him.”

His father, Chris Childers, spoke of the medical hardships his son endured.

“Through it all, he had this disposition about him that he could just overcome,” he said.“He never quit and he never gave up and he was always smiling.”

Austin with his parents and brother Garrett.

When visitors went to see him, Chris Childers said his son “would always turn it around and say, ‘Tell me what’s going on in your life.’ It was always about others. And it was always about putting someone before himself and never, ever complaining. … He was just born that way to have this internal optimistic view of life.”

Among those who visited him in the hospital were Alana “Honey Boo Boo” Thompson and her family. Actor Aaron Paul stopped by while filming the movie “Need for Speed” in downtown Macon. Comedian Durwood “Mr. Doubletalk” Fincher had also been a frequent visitor and had become a special friend of the family.

Few have known adversity like Austin, who was diagnosed with mitochondrial disease when he was playing football at First Presbyterian Day School (Macon, GA) in the seventh grade.

First Presbyterian Day School football

In late August, FPD dedicated the football field to Childers, who never played forthe Vikings past the seventh grade due to his condition, yet served as team captain and attended every game when he was able.

Greg Moore, FPD’s athletics director, on spoke of the football field that now bears Childers’ name and what his courage and determination might mean to future students and athletes.

“Austin, for all who know him and his family, is a picture of faith and perseverance,” Moore said. “Our hope is that for generations the story of how he handled what looked like all of life’s toughest circumstances will be something to be praised and cherished.”

Moore added, “There’s a lot of lessons there that go way beyond an athletic field. But certainly, athletic teams, for a long time, should be taught that there is a way to handle adversity, and do so in a way that has a positive impact on everyone around you. And that’s the story of Austin Childers.”

First Presbyterian Day School field dedication on Aug. 30, 2014.

Austin’s remains will be donated to aid in research for the disease.

One in 2,500 are affected by mitochondrial disease. It’s a complex, under diagnosed disease that may appear at anytime – at birth, in the teen years or as an adult. To learn more about mitochondrial disease, please visit hopeflies.org.

Please note: FMM reached out to Chris Childers approximately three days before Austin’s death. The above article is from the Macon Telegraph and photos are from Prayers for Austin Childers, Austin’s Facebook support group.

Breast Cancer and Mitochondrial Disease

A reduction in mitochondrial DNA (mtDNA) content leads to more aggressive forms of breast cancer, according to researchers from the University of Pennsylvania.

The study, published in the journal Oncogene, breaks new ground in understanding why some cancers progress and spread faster than others and may offer clinicians a biomarker that would distinguish patients with particularly aggressive forms of disease, helping personalize treatment approaches.

The work was led by the Penn School of Veterinary Medicine’s Manti Guha, a senior research investigator, and Narayan Avadhani, Harriet Ellison Woodward Professor of Biochemistry in the Department of Animal Biology.

These researchers were able to show the connection between the amounts of mtDNA in a cell and why some forms of breast cancer metastasize faster and have poorer prognosis.

Use of mtDNA as a biomarker could help distinguish patients with aggressive forms of the disease so treatment approaches could be personalized for potentially better outcomes.

“Most patients who had low copy numbers of mitochondrial DNA have a poor disease prognosis,” said Guha. “We’ve shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease.”

Mitochondria, the “powerhouses” of mammalian cells, are also a signaling hub. They are heavily involved in cellular metabolism as well as in apoptosis, the process of programmed cell death by which potentially cancerous cells can be killed before they multiply and spread. In addition, mitochondria contain their own genomes, which code for specific proteins and are expressed in coordination with nuclear DNA to regulate the provision of energy to cells.

For the study, the researchers purposefully reduced the amount of mtDNA in a cell using two methods: chemical and genetic. Then, they compared normal, non–cancer-forming human breast tissue cells with cancerous breast cells for both methods to compare the altered cells with unmanipulated mtDNA.

“Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells,” Avadhani said. “These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body.”

When mtDNA was reduced, the cells appeared disorganized and more like that of metastatic cancer cell. Even non–tumor-forming breast cells started to more closely resemble cancer cells. Plus, the reduced-mtDNA cells became self-renewing and had characteristics of breast cancer stem cells.

Next, the researchers plan to extend this study to in vivo mouse models and will also investigate these mechanisms in tumor samples from human breast cancer patients.

To learn more about the mitochondria and how it effects the body, visit hopeflies.org.

MRT Treatment for Autism

According to the U.S. Centers for Disease Control and Prevention (CDC), the number of patients diagnosed with autism each year is increasing rapidly. Autism is categorized as a neurodevelopmental disorder, which delays and interrupts normal cognitive development and expression. There is currently no commonly accepted standard to treat autism. Available treatments include behavioral modification, speech and occupational therapies, and psychological and nutritional counseling. Psychotropic medication is an optional medical treatment for individuals with severe symptoms, such as epileptic seizure or self-injurious behavior.

The Brain Treatment Center provides a new alternative treatment using advanced electromagnetic technology focused on transforming the biological, behavioral, and medical aspects of autism.

The technology developed at Brain Treatment Center, known as Magnetic Resonance Therapy (MRTSM therapy), is a non-invasive and painless treatment. Magnetic Resonance Therapy combines EEG, brain stimulation, Neurofeedback, EKG and other biometric techniques to provide a highly customized treatment personalized to how a patient’s brain takes in, processes, and communicates information.

This treatment directly addresses neural deficits common in autism and directs brain activity towards a more neurotypical state.

Visit braintreatmentcenter.com to learn more about the Brain Treatment Center and Magnetic Resistance Therapy. To learn more about Mitochondrial Disease how it is related to Autism, click here.